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1.  Ischemic Colitis after Cardiac Surgery: Can We Foresee the Threat? 
PLoS ONE  2016;11(12):e0167601.
Ischemic colitis (IC) remains a great threat after cardiac surgery with use of extracorporeal circulation. We aimed to identify predictive risk factors and influence of early catecholamine therapy for this disease.
We prospectively collected and analyzed data of 224 patients, who underwent laparotomy due to IC after initial cardiac surgery with use of extracorporeal circulation during 2002 and 2014. For further comparability 58 patients were identified, who underwent bypass surgery, aortic valve replacement or combination of both. Age ±5 years, sex, BMI ± 5, left ventricular function, peripheral arterial disease, diabetes and urgency status were used for match-pair analysis (1:1) to compare outcome and detect predictive risk factors. Highest catecholamine doses during 1 POD were compared for possible predictive potential.
Patients’ baseline characteristics showed no significant differences. In-hospital mortality of the IC group with a mean age of 71 years (14% female) was significantly higher than the control group with a mean age of 70 (14% female) (67% vs. 16%, p<0.001). Despite significantly longer bypass time in the IC group (133 ± 68 vs. 101 ± 42, p = 0.003), cross-clamp time remained comparable (64 ± 33 vs. 56 ± 25 p = 0.150). The majority of the IC group suffered low-output syndrome (71% vs. 14%, p<0.001) leading to significant higher lactate values within first 24h after operation (55 ± 46 mg/dl vs. 31 ± 30 mg/dl, p = 0.002). Logistic regression revealed elevated lactate values to be significant predictor for colectomy during the postoperative course (HR 1.008, CI 95% 1.003–1.014, p = 0.003). However, Receiver Operating Characteristic Curve calculates a cut-off value for lactate of 22.5 mg/dl (sensitivity 73% and specificity 57%). Furthermore, multivariate analysis showed low-output syndrome (HR 4.301, CI 95% 2.108–8.776, p<0.001) and vasopressin therapy (HR 1.108, CI 95% 1.012–1.213, p = 0.027) significantly influencing necessity of laparotomy.
Patients who undergo laparotomy for IC after initial cardiac surgery have a substantial in-hospital mortality risk. Early postoperative catecholamine levels do not influence the development of an IC except vasopressin. Elevated lactate remains merely a vague predictive risk factor.
PMCID: PMC5157983  PMID: 27977704
2.  Detection of Human Papillomavirus Infection in Patients with Vaginal Intraepithelial Neoplasia 
PLoS ONE  2016;11(12):e0167386.
Vaginal intraepithelial neoplasia (VAIN) is a pre-malignant lesion, potentially leading to vaginal cancer. It is a rare disease, representing less than 1% of all intraepithelial neoplasia of the female genital tract. Similar to cervical intraepithelial neoplasia (CIN), there are three different grades of VAIN. VAIN 1 is also known as a low-grade squamous intraepithelial lesion (LSIL), whereas VAIN 2 and VAIN 3 both represent high-grade squamous intraepithelial lesions (HSIL). Risk factors for the development of VAIN are similar to those for cervical neoplasia, i.e. promiscuity, starting sexual activity at an early age, tobacco consumption and infection with human papillomavirus (HPV). However, compared to other intraepithelial neoplasia such as CIN or VIN (vulvar intraepithelial neoplasia), there still is little understanding about the natural course of VAIN and its capacity for pro- or regression. Furthermore, there is controversial data about the HPV detection rate in VAIN lesions.
Patients and Methods
67 patients with histologically confirmed VAIN, who were diagnosed between 2003 and 2011 at the University Women´s Hospital of Heidelberg Germany, were included in this study. The biopsies of all participating patients were subjected to HPV genotyping. GP-E6/E7 Nested Multiplex PCR (NMPCR) was used to identify and genotype HPV. Eighteen pairs of type-specific nested PCR primers were assessed to detect the following "high-risk" HPV genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, as well as the "low-risk" genotypes 6/11, 42, 43 and 44. The data was analyzed with the software SAS (Statistical Analysis System).
All 67 cases were eligible for DNA analysis. The median age was 53 years. The largest group with 53% (n = 36) was formed by women, who were first diagnosed with VAIN between the age of 41 to 60 years. 50% (n = 37) of the patients presented a VAIN in the upper 1/3 of the vagina. 58 (87%) were diagnosed with HSIL (VAIN). The median age in patients with LSIL (VAIN) was 53 years and in patients with HSIL (VAIN) 53.5 years. 12 women (18%) had an immunosuppression. HPV positivity was confirmed in 37 patients (55%). Except for a single patient, who had a triple infection with HPV types 6/11, 16 and 68, only infections with one single HPV genotype were detected. An infection with the HPV genotypes 31, 39, 45, 51, 58, 59, 66, 42, 43 and 44 couldn’t be found in any of the patients. In 28 patients with diagnosed VAIN, an infection with HPV 16 could be shown, 24 (86%) of them were diagnosed with a HSIL (VAIN). 16 (24%) women presented condylomata and 13 of them (81%) had a positive HPV status. However, only 47% of the women without condylomata presented a positive HPV status, resulting in a significant correlation (p = 0.0164) between condylomata and HPV infection. In 28 of all 67 patients (42%), recurrence of the neoplasia occurred.
HPV 16 is the main virus-type to be associated with the development of a VAIN. Also, HPV 16 infection, VIN or condylomata acuminata in the past medical history seemed to be significant factors for early relapse.
PMCID: PMC5132291  PMID: 27907089
3.  Resistance training concomitant to radiotherapy of spinal bone metastases – survival and prognostic factors of a randomized trial 
To compare the effects of resistance training versus passive physical therapy on bone survival in the metastatic bone during radiation therapy (RT) as combined treatment in patients with spinal bone metastases. Secondly, to evaluate overall survival and progression-free-survival (PFS) as well as to quantify prognostic factors of bone survival after combined treatment.
In this randomized trial 60 patients were allocated from September 2011 until March 2013 into one of the two groups: resistance training (group A) or passive physical therapy (group B) with thirty patients in each group during RT. We estimated patient survival using Kaplan-Meier survival method. The Wald-test was used to evaluate the prognostic importance of pathological fracture, primary site, Karnofsky performance status, localization of metastases, number of metastases, and cerebral metastases.
Median follow-up was 10 months (range 2–35). Bone survival showed no significant difference between groups (p = .303). Additionally no difference between groups could be detected in overall survival (p = .688) and PFS (p = .295). Local bone progression was detected in 16.7 % in group B, no irradiated bone in group A showed a local progression over the course (p = 0.019). In univariate analysis breast cancer, prostate cancer, and the presence of cerebral metastases had a significant impact on bone survival in group B, while no impact could be demonstrated in group A.
In this group of patients with spinal bone metastases we were able to show that guided resistance training of the paravertebral muscles had no essential impact on survival concomitant to RT. Importantly, no local bone progression in group A was detected, nevertheless no prognostic factor for combined treatment could be evaluated.
Trial registration
Clinical trial identifier NCT 01409720. Registered 8 February 2011.
PMCID: PMC4963927  PMID: 27464793
Bone metastases; Spine; Resistance training; Survival; Palliative radiotherapy
4.  Acupuncture to improve tolerance of diagnostic esophagogastroduodenoscopy in patients without systemic sedation: results of a single-center, double-blinded, randomized controlled trial (DRKS00000164) 
Trials  2016;17:350.
Sedation prior to esophagogastroduodenoscopy is widespread and increases patient comfort. However, it demands additional trained personnel, accounts for up to 40 % of total endoscopy costs and impedes rapid hospital discharge. Most patients lose at least one day of work. 98 % of all serious adverse events occurring during esophagogastroduodenoscopy are ascribed to sedation. Acupuncture is reported to be effective as a supportive intervention for gastrointestinal endoscopy, similar to conventional premedication. We investigated whether acupuncture during elective diagnostic esophagogastroduodenoscopy could increase the comfort of patients refusing systemic sedation.
We performed a single-center, double-blinded, placebo-controlled superiority trial to compare the success rates of elective diagnostic esophagogastroduodenoscopies using real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic esophagogastroduodenoscopy who refused systemic sedation were eligible; 354 patients were randomized. The primary endpoint measure was the rate of successful esophagogastroduodenoscopies. The intervention was real or placebo acupuncture before and during esophagogastroduodenoscopy. Successful esophagogastroduodenoscopy was based on a composite score of patient satisfaction with the procedure on a Likert scale as well as quality of examination, as assessed by the examiner.
From February 2010 to July 2012, 678 patients were screened; 354 were included in the study. Baseline characteristics of the two groups showed a similar distribution in all but one parameter: more current smokers were allocated to the placebo group. The intention-to-treat analysis included 177 randomized patients in each group. Endoscopy could successfully be performed in 130 patients (73.5 %) in the real acupuncture group and 129 patients (72.9 %) in the placebo group. Willingness to repeat the procedure under the same conditions was 86.9 % in the real acupuncture group and 87.6 % in the placebo acupuncture group.
Esophagogastroduodenoscopy without sedation is safe and can successfully be performed in two-thirds of patients. Patients planned for elective esophagogastroduodenoscopy without sedation do not benefit from acupuncture of the Sinarteria respondens (Rs) 24 Chengjiang middle line, Pericard (Pc) 6 Neiguan bilateral, or Dickdarm (IC) 4 Hegu bilateral, according to traditional Chinese medicine meridian theory.
Trial registration
DRKS00000164. Registered on 10 December 2009.
PMCID: PMC4960815  PMID: 27455961
Acupuncture; endoscopy; esophagogastroduodenoscopy; sedation
5.  Survival and prognostic factors in patients with stable and unstable spinal bone metastases from solid tumors: a retrospective analysis of 915 cases 
BMC Cancer  2016;16:528.
Adequate prediction of survival plays an important role in treatment decisions for patients with spinal bone metastases (SBM). Several prognostic factors are already used in daily clinical practice, but factors related to stability of SBM are still unknown. Therefore, we designed this study to identify these prognostic factors.
We retrospectively assessed 915 patients from solid tumors with commonly metastased into the bone treated at our department between January 2000 and January 2012. Lung cancer (NSCLC), breast and renal cancer listed in Table 1 are the most common solid tumors with bone metastasis in this study. Prostate carcinoma was excluded due to osteoblastic SBM with no influence for stability. We calculated overall survival (OS) and bone survival (BS; time between first diagnosis of bone metastases until death) with the Kaplan-Meier method and assessed prognostic factors for BS with the log-rank test and a Cox regression model separately for patients with stable and unstable SBM.
Median follow-up was 9.3 months. OS after 6 months, 1, 2, and 5 years was 81, 62, 42, and 25 % in patients with stable SBM and 78, 57, 38, and 22 % in patients with unstable SBM (p = 0.851). BS was 57, 38, 22, and 5 % in the group of stable SBM after 6 months, 1, 2, and 5 years. For patients with unstable SBM BS after 6 months, 1, 2, and 5 years was 59, 39, 19, and 8 % (p = 0.755). In multivariate analysis we found male gender (HR = 1.27 [95 % CI 1.01–1.60], p = 0.04), Karnofsky performance status (KPS) <80 % (HR = 1.27 [95%CI 1.04–1.55], p = 0.02) and non-small cell lung cancer (NSCLC; HR = 2.77 [95%CI 1.99–3.86], p < 0.0001) to be independent prognostic factors for shortened survival in patients with stable SBM. Independent prognostic factors for unstable SBM were age per year (HR = 1.01 [95 % CI 1.0–1.02], p = 0.025), multiple SBM (HR = 1.35 [95 % CI 1.1–1.65], p = 0.003), and NSCLC (HR = 2.0 [95 % CI 1.43–2.80], p < 0.0001). Additionally, not wearing an orthopedic corset (HR = 0.77 [95 % CI 0.62–0.96], p = 0.02) was associated with prolonged BS in patients with unstable SBM and in both groups BS was significantly longer in patients without liver metastases (stable SBM: HR = 0.72 [95 % CI 0.56–0.92], p = 0.008; unstable SBM: HR = 0.71 [95 % CI 0.54–0.92], p = 0.01).
Survival was equal for patients with stable and unstable SBM. However, prognostic factors differed in both groups and stability should therefore be considered in treatment decision-making.
PMCID: PMC4960720  PMID: 27456003
Prognostic factors; Stability; Survival; Spinal bone metastases
6.  Failed treatment of long bone nonunions with low intensity pulsed ultrasound 
The use of low intensity pulsed ultrasound (LIPUS) in the treatment of nonunions is still controversial. The present study is concerned with whether this procedure has a clinical use and which cofactors influence its therapeutic results.
In this prospective, single institution, observational study, data from October 2010 to October 2013 from 61 nonunions in 60 patients treated with EXOGEN® LIPUS therapy were analysed. The average age was 45.4 ± 9.81 (18–63) years. Treatment was primarily done on long bones of the lower extremity (75.4 %). All 61 nonunions were examined after treatment, and the rate of healing as well as functional and subjective results were evaluated. Based on clinical and radiological findings, patients were divided into two groups: G1—successful treatment; and G2—unsuccessful treatment. Groups were compared to one another to identify possible factors influencing treatment.
Twenty (32.8 %) patients showed bone consolidation with an average time of healing of 5.3 (2–7) months. In patients without successful treatment, who underwent revision surgery instead, full weight bearing took on average 3.7 months longer, and they were able to return to work 6.8 months later. Most of the treated patients (70.5 %) reported no improvement in pain. In G2, 12 (29.3 %) patients suffered in their previous history from osteitis; in G1 there were only two patients (10 %) (p = 0.012). There were further significant differences in the age of the fracture, the type of osteosynthesis, the gap size, as well as the NUSS score.
Despite patients being chosen strictly according to EXOGEN® indications, only a small number of patients with nonunions who underwent LIPUS therapy experienced successful treatment (32.8 %). Overall, its use resulted in a clear delay in the time of treatment, so that according to our results, the use of LIPUS should be seen critically in long bone nonunions and use should be made on a case-by-case basis.
PMCID: PMC4945690  PMID: 27383218
Nonunion; Delayed fracture healing; Low intensity pulsed ultrasound; LIPUS; EXOGEN®
7.  Intravenous versus epidural analgesia to reduce the incidence of gastrointestinal complications after elective pancreatoduodenectomy (the PAKMAN trial, DRKS 00007784): study protocol for a randomized controlled trial 
Trials  2016;17:194.
Despite substantial improvements in surgical and anesthesiological practices leading to decreased mortality of less than 5 % at high-volume centers, pancreatic surgery is still associated with high morbidity rates of up to 50 %. Attention is increasingly directed toward the optimization of perioperative management to reduce complications and enhance postoperative recovery. Currently, two different strategies for postoperative pain management after pancreatoduodenectomy are being routinely used: patient-controlled intravenous analgesia and thoracic epidural analgesia. Evidence is lacking to assess which strategy entails fewer postoperative complications.
The PAKMAN trial is designed as an adaptive, pragmatic, randomized, controlled, multicenter, open-label, superiority trial with two parallel study groups. A total of 370 patients scheduled for elective pancreatoduodenectomy will be randomized after giving written informed consent, and 278 patients are needed for analysis. Patients with chronic pancreatitis, severe chronic obstructive pulmonary disease (COPD), American Society of Anesthesiologists (ASA) physical status classification ≥ IV, or chronic pain syndrome will be excluded. The group A intervention includes intraoperative general anesthesia and postoperative patient-controlled intravenous analgesia; the group B intervention comprises combined intraoperative general anesthesia and epidural analgesia with postoperative epidural analgesia. The primary endpoint of this trial is a composite of the gastrointestinal complications (delayed gastric emptying, pancreatic fistula, biliary leak, gastrointestinal bleeding, and postoperative ileus) up to postoperative day 30. The aim is to investigate whether the frequency of gastrointestinal complications following pancreatoduodenectomy can be reduced by 15 % using postoperative, patient-controlled intravenous analgesia compared with epidural analgesia.
Several previous studies investigating the two different strategies for postoperative pain management have mainly focused on their effectiveness in pain control. However, the PAKMAN trial is the first to compare them with regard to their impact on the surgical endpoint “postoperative gastrointestinal complications” after pancreatoduodenectomy.
Trial registration
German Clinical Trials Register, DRKS00007784
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1306-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4827246  PMID: 27068582
Epidural analgesia; Patient-controlled intravenous analgesia; Pancreatoduodenectomy; Postoperative pain management; Postoperative complication; Randomized controlled trial
8.  Immediate tumor resection in patients with locally advanced gastroesophageal adenocarcinoma with nonresponse to chemotherapy after 4 weeks of treatment versus resection after completion of chemotherapy (OPTITREAT trial, DRKS00004668): study protocol for a randomized controlled pilot trial 
Neoadjuvant chemotherapy is a standard of care for patients with adenocarcinoma of the esophagus and stomach in Europe, but still only 20–40 % respond to therapy and the critical issue; how to treat nonresponding patients is still unclear. So far, there is no randomized trial evaluating the impact of early termination of neoadjuvant chemotherapy and immediate tumor resection in nonresponding patients with locally advanced gastroesophageal cancer on postoperative outcome. With this exploratory pilot trial, we want to get first estimates about the effect of discontinuation of chemotherapy with the aim to plan and conduct a further definitive trial.
OPTITREAT is designed as a single-center, randomized controlled pilot trial with two parallel study groups. Four weeks after starting neoadjuvant chemotherapy in all patients, clinical response will be assessed by endoscopy and endosonographic ultrasound. Then, nonresponding patients (n = 84) will be randomized in a 1:1 ratio to intervention group with stopping chemotherapy and immediate tumor resection or control group with completion of chemotherapy before surgery. Outcome measures are overall survival, R0 resection rate, perioperative morbidity and mortality, histopathological response, and quality of life. Statistical analysis will be based on the intention-to-treat population. Due to the study design as an explorative pilot trial, no formal sample size calculation was performed. The planned total sample size of 120 patients is considered ethical and large enough to show the feasibility and safety of the concept. First data on differences between the study groups in the defined endpoints will also be generated.
Individualized therapy is of utmost interest in the treatment of locally advanced gastroesophageal adenocarcinoma as less than half of the patients show objective response to current chemotherapy regimens. The findings of the OPTITREAT trial will help to get first data about clinical response evaluation followed by immediate tumor resection in nonresponding patients after 4 weeks of neoadjuvant chemotherapy. Based on the results of this pilot study, a future confirmatory trial will be planned to prove efficacy and evaluate significance.
Trial registration
German Clinical Trial Register number: DRKS00004668
PMCID: PMC5153833  PMID: 27965838
Esophagogastric cancer; Neoadjvuant chemotherapy; Response evaluation
9.  Biochemical markers of bone turnover in patients with spinal metastases after resistance training under radiotherapy – a randomized trial 
BMC Cancer  2016;16:231.
To compare the effects of resistance training versus passive physical therapy on bone turnover markers (BTM) in the metastatic bone during radiation therapy (RT) in patients with spinal bone metastases. Secondly, to evaluate an association of BTM to local response, skeletal-related events (SRE), and number of metastases.
In this randomized trial, 60 patients were allocated from September 2011 to March 2013 into one of the two arms: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each arm during RT. Biochemical markers such as pyridinoline (PYD), desoxy-pyridinoline (DPD), bone alkaline phosphatase (BAP), total amino-terminal propeptide of type I collagen (PINP), beta-isomer of carboxy-terminal telopeptide of type I collagen (CTX-I), and cross-linked N-telopeptide of type I collagen (NTX) were analyzed at baseline, and three months after RT.
Mean change values of PYD and CTX-I were significantly lower at 3 months after RT (p = 0.035 and p = 0.043) in Arm A. Importantly, all markers decreased in both arms, except of PYD and CTX-I in arm B, although significance was not reached for some biomarkers. In arm A, the local response was significantly higher (p = 0.003) and PINP could be identified as a predictor for survivors (OR 0.968, 95%CI 0.938–0.999, p = 0.043). BAP (OR 0.974, 95%CI 0.950–0.998, p = 0.034) and PINP (OR 1.025, 95%CI 1.001–1.049, p = 0.044) were related with an avoidance of SRE.
In this group of patients with spinal bone metastases, we were able to show that patients with guided resistance training of the paravertebral muscles can influence BTM. PYD and CTX-I decreased significantly in arm A. PINP can be considered as a complementary tool for prediction of local response, and PINP as well as BAP for avoidance of SRE.
Trial registration
Clinical trial identifier NCT 01409720. August 2, 2011.
PMCID: PMC4794897  PMID: 26983672
Bone metastases; Spine; Physical exercise; Biochemical markers; Resistance training
10.  Ultrasound vs. MRI in the assessment of rotator cuff structure prior to shoulder arthroplasty 
Journal of Orthopaedics  2015;12(1):23-30.
We compared the accuracy of US to 3 T Tesla MRI for the detection of rotator cuff and long biceps tendon pathologies before joint replacement.
45 patients were prospectively included.
For the supraspinatus tendon, the accuracy of US when using MRI as reference was 91.1%. For the infraspinatus tendon, the accuracy with MRI as reference was 84.4%. The subscapularis tendon was consistently assessed by US and MRI in 35/45 patients (accuracy 77.8%). For the long biceps tendon the accuracy was 86.7%.
US detection of rotator cuff and biceps tendon integrity is comparable to MRI and should be preferred in revision cases.
PMCID: PMC4354568  PMID: 25829757
Rotator cuff; Ultrasound; MRI; Shoulder; Supraspinatus
11.  Mesopancreatic Stromal Clearance Defines Curative Resection of Pancreatic Head Cancer and Can Be Predicted Preoperatively by Radiologic Parameters 
Medicine  2016;95(3):e2529.
Supplemental Digital Content is available in the text
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a strong fibrotic stromal reaction and diffuse growth pattern. Peritumoral fibrosis is often evident during surgery but only distinguishable from tumor by microscopic examination. The aim of this study was to investigate the role of clearance of fibrotic stromal reaction at the mesopancreatic resection margin as a criterion for radical resection and preoperative assessment of resectability.
Mesopancreatic stromal clearance status (S-status) was defined as the presence or absence (S+/S0) of fibrotic stromal reaction at the mesopancreatic resection margin. Detailed retrospective clinicopathologic re-evaluation of margin status and preoperative cross-sectional imaging was performed in a cohort of 91 patients operated for pancreatic head PDAC from 2001 to 2011.
Conventional margin positive resection (R+, tumor cells directly at the margin) was found in 36%. However, S-status further divided the margin negative (R0) group into patients with median survival of 14 months versus 31 months (S+ versus S0, P = 0.005). Overall rate of S+ was 53%. S-status and lymph node ratio constituted the only independent predictors of survival. Stranding of the superior mesenteric artery fat sheath was the only independent radiologic predictor of S+ resection, and achieved a 71% correct prediction of S-status.
Mesopancreatic stromal clearance is a major determinant of curative resection in PDAC, and preoperative prediction by cross-sectional imaging is possible, setting the basis for a new definition of borderline resectability.
PMCID: PMC4998270  PMID: 26817896
12.  Sequential learning of psychomotor and visuospatial skills for laparoscopic suturing and knot tying – study protocol for a randomized controlled trial “The shoebox study” 
Trials  2016;17:14.
Laparoscopy training has become an integral part of surgical education. Suturing and knot tying is a basic, yet inherent part of many laparoscopic operations, and should be mastered prior to operating on patients. One common and standardized suturing technique is the C-loop technique. In the standard training setting, on a box trainer, the trainee learns the psychomotor movements of the task and the laparoscopic visuospatial orientation simultaneously. Learning the psychomotor and visuospatial skills separately and sequentially may offer a more time-efficient alternative to the current standard of training.
This is a monocentric, two-arm randomized controlled trial. The participants are medical students in their clinical years (third to sixth year) at Heidelberg University who have not previously partaken in a laparoscopic training course lasting more than 2 hours. A total of 54 students are randomized into one of two arms in a 1:1 ratio to sequential learning (group 1) or control (group 2). Both groups receive a standardized introduction to the training center, laparoscopic instruments, and C-loop technique. Group 1 learn the C-loop using a transparent shoebox, thus only learning the psychomotor skills. Once they reach proficiency, they then perform the same knot tying procedure on a box trainer with standard laparoscopic view, where they combine their psychomotor skills with the visuospatial orientation inherent to laparoscopy. Group 2 learn the C-loop using solely a box trainer with standard laparoscopic view until they reach proficiency. Trainees work in pairs and time is recorded for each attempt. The primary outcome is mean total training time for each group. Secondary endpoints include procedural and knot quality subscore differences. Tertiary endpoints include studying the influence of gender and video game experience on performance.
This study addresses whether the learning of the psychomotor and visuospatial aspects of laparoscopic suturing and knot tying is optimal sequentially or simultaneously, by assessing total training time, procedural, and knot quality differences between the two groups. It will improve the efficiency of future laparoscopic suturing courses and may serve as an indicator for laparoscopic training in a broader context, i.e., not only for suturing and knot tying.
Trial registration
This trial was registered on 12 August 2015 with the trial registration number DRKS00008668.
PMCID: PMC4704418  PMID: 26739331
Laparoscopy; Training; Education; Minimally invasive surgery; Suturing; Knot tying
13.  Detection of carcinogenic etheno-DNA adducts in children and adolescents with non-alcoholic steatohepatitis (NASH) 
Carcinogenic exocyclic-DNA adducts like 1,N6-etheno-2'-deoxyadenosine (εdA) are formed through reactive intermediates of 4-hydroxynonenal (4-HNE) or other lipid peroxidation (LPO) products with the DNA bases A, C, methyl-C and G. High levels of hepatic etheno-DNA adducts have been detected in cancer prone liver diseases including alcoholic liver disease (ALD). In ALD εdA levels correlated significantly with cytochrome P-450 2E1 (CYP2E1) expression which is also induced in non-alcoholic steatohepatitis (NASH). We investigated the occurrence of εdA adducts in children with NASH as a DNA damage marker.
Liver biopsies from 21 children/adolescents with histologically proven NASH were analysed for hepatic fat content, inflammation, and fibrosis. εdA levels in DNA, CYP2E1-expression and protein bound 4-hydroxynonenal (HNE) were semi-quantitatively evaluated by immunohistochemistry.
Among 21 NASH children, εdA levels in the liver were high in 3, moderate in 5, weak in 9 and not elevated in 4 patients. There was a positive correlation between CYP2E1 and protein-bound 4-HNE (r=0.60; P=0.008) and a trend for a positive relationship for CYP2E1 vs. staining intensity of εdA (r=0.45; P=0.06). Inflammatory activity and fibrosis correlated significantly (r=0.49, P=0.023).
Our results demonstrate for the first time the presence of elevated carcinogenic etheno-DNA lesions (εdA) in the majority (17/21) of liver biopsies from young NASH patients. Our data suggest that LPO-derived etheno-adducts are implicated in NASH. Whether these adducts may serve as predictive risk markers in NASH children to develop hepatocellular cancer later in life remains to be investigated.
PMCID: PMC4689692  PMID: 26734629
Cytochrome P-450 2E; etheno-DNA adducts; hepatocellular cancer; lipidperoxidation-induced DNA damage; non-alcoholic steatohepatitis in children (NASH in children)
14.  Nutritional Risk in Major Abdominal Surgery: Protocol of a Prospective Observational Trial to Evaluate the Prognostic Value of Different Nutritional Scores in Pancreatic Surgery 
JMIR Research Protocols  2015;4(4):e132.
The influence of patients’ preoperative nutritional status on their clinical outcome has already been proven. Therefore, patients with malnutrition are in need of additional therapeutic efforts. However, for pancreatic surgery, evidence suggesting the adequacy of existing nutritional assessment scores to estimate malnutrition associated with postoperative outcome is limited.
The aim of the observational trial “Nutritional Risk in Major Abdominal Surgery (NURIMAS) Pancreas” is to prospectively assess and analyze different nutritional assessment scores for their prognostic value on postoperative complications in patients undergoing pancreatic surgery.
All patients scheduled to receive elective pancreatic surgery at the University Hospital of Heidelberg will be screened for eligibility. Preoperatively, 12 nutritional assessment scores will be collected and patients will be assigned either at risk or not at risk for malnutrition. The postoperative course will be followed prospectively and complications according to the Clavien-Dindo classification will be recorded. The prognostic value for complications will be evaluated for every score in a univariable and multivariable analysis corrected for known risk factors in pancreatic surgery.
Final data analysis is expected to be available during Spring 2016.
The NURIMAS Pancreas trial is a monocentric, prospective, observational trial aiming to find the most predictive clinical nutritional assessment score for postoperative complications. Using the results of this protocol as a knowledge base, it is possible to conduct nutritional risk-guided intervention trials to prevent postoperative complications in the pancreatic surgical population.
Trial Registration DRKS00006340; (Archived by WebCite at
PMCID: PMC4704883  PMID: 26573991
Diagnosis Related Group system; malnutrition; nutritional assessment; nutritional score; pancreatic surgery
15.  The influence of orthopedic corsets on the incidence of pathological fractures in patients with spinal bone metastases after radiotherapy 
BMC Cancer  2015;15:745.
Clinical care of unstable spinal bone metastases in many centers often includes patient immobilization by means of an orthopedic corset in order to prevent pathological fractures. The aim of this retrospective analysis was to evaluate the incidence of pathological fractures after radiotherapy (RT) in patients with and without orthopedic corsets and to assess prognostic factors for pathological fractures in patients with spinal bone metastases.
The incidence of pathological fractures in 915 patients with 2.195 osteolytic metastases in the thoracic and lumbar spine was evaluated retrospectively on the basis of computed tomography (CT) scans between January 2000 and January 2012 depending on prescription and wearing of patient—customized orthopedic corsets.
In the corset group, 6.8 and 8.0 % in no-corset group showed pathological fractures prior to RT, no significant difference between groups was detected (p = 0.473). After 6 months, patients in the corset group showed pathological fractures in 8.6 % and in no-corset group in 9.3 % (p = 0.709). The univariate and bivariate analyses demonstrated no significant prognostic factor for incidence of pathological fractures in both groups.
In this analysis, we could show for the first time in more than 900 patients, that abandoning a general corset supply in patients with spinal metastases does not significantly cause increased rates of pathological fractures. Importantly, the incidence of pathological fracture after RT was small.
PMCID: PMC4612425  PMID: 26486754
16.  Long-term durability of alumina ceramic heads in THA 
The optimal type of bearing for hip arthroplasty remains a matter of debate. Ceramic-on-polyethylene (CoP) bearings are frequently used in younger and more active patients to reduce wear and increase biocompatibility compared to Metal-on-Polyethylene (MoP) bearings. However, in comparison to metal heads, the fracture risk of ceramic heads is higher. In addition, ceramic head fractures pose a serious complication which often necessitates major revision surgery. To date, there are no long-term data (>20 years of follow-up) reporting fracture rates of the ceramic femoral heads in CoP bearings. The purpose of this research was to investigate long-term CoP fracture rate.
We evaluated the clinical and radiographic results of 348 cementless THAs treated with 2nd generation Biolox® Al2O3 Ceramic-on-Polyethylene (CoP) bearings consecutively implanted between January 1985 and December 1989. The mean age at implantation was 57 years. The patients were followed for a minimum of 20 years. At the final 111 had died, and 5 were lost to follow-up. The cumulative incidence of ceramic head fractures in the long-term was estimated using a competing risk analysis.
The cumulative incidence of ceramic head fracture after 22-years was estimated with a competing risk analysis at 0.29 % after 22-years (SE = 2.09 %; 95 % - CI: 0.03-1.5 %). The radiographic analysis revealed no impending failures at final follow-up.
The fracture rate of second-generation ceramic heads using a CoP articulation remains very low into the third decade after cementless THA.
PMCID: PMC4567834  PMID: 26363981
Bearings; Ceramic; Polyethylene; Hip Arthroplasty; THA; Hip Replacement; THR
17.  BariSurg trial: Sleeve gastrectomy versus Roux-en-Y gastric bypass in obese patients with BMI 35–60 kg/m2 – a multi-centre randomized patient and observer blind non-inferiority trial 
BMC Surgery  2015;15:87.
Roux-en-Ygastric bypass (RYGB) and sleeve gastrectomy (SG) rank among the most frequently applied bariatric procedures worldwide due to their positive risk/benefit correlation. A systematic review revealed a similar excess weight loss (EWL) 2 years postoperatively between SG and RYGB. However, there is a lack of randomized controlled multi-centre trials comparing SG and RYGB, not only concerning EWL, but also in terms of remission of obesity-related co-morbidities, gastroesophageal reflux disease (GERD) and quality of life (QoL) in the mid- and long-term.
The BariSurg trial was designed as a multi-centre, randomized controlled patient and observer blind trial. The trial protocol was approved by the corresponding ethics committees of the centres. To demonstrate EWL non-inferiority of SG compared to RYGB, power calculation was performed according to a non-inferiority study design. Morbidity, mortality, remission of obesity-related co-morbidities, GERD course and QoL are major secondary endpoints. 248 patients between 18 and 70 years, with a body mass index (BMI) between 35–60 kg/m2 and indication for bariatric surgery according to the most recent German S3-guidelines will be randomized. The primary and secondary endpoints will be assessed prior to surgery and afterwards at discharge and at the time points 3–6, 12, 24, 36, 48 and 60 months postoperatively.
With its five year follow-up, the BariSurg-trial will provide further evidence based data concerning the impact of SG and RYGB on EWL, remission of obesity-related co-morbidities, the course of GERD and QoL.
Trial registration
The trial protocol has been registered in the German Clinical Trials Register DRKS00004766.
PMCID: PMC4506636  PMID: 26187377
Sleeve gastrectomy; Roux-en-Ygastric bypass; Randomized controlled trial; Patient and observer blind trial; Long-term excess weight loss; Obesity related co-morbidity; Gastroesophageal reflux disease; Quality of life; Morbidity; Mortality
18.  Prognostic factors for survival of women with unstable spinal bone metastases from breast cancer 
Bone metastases are an important clinical issue in women with breast cancer. Particularly, unstable spinal bone metastases (SBM) are a major cause of severe morbidity and reduced quality of life (QoL) due to frequent immobilization. Radiotherapy (RT) is the major treatment modality and is capable of promoting re-ossification and improving stability. Since local therapy response is excellent, survival of these patients with unstable SBM is of high clinical importance. We therefore conducted this analysis to assess survival and to determine prognostic factors for bone survival (BS) in women with breast cancer and unstable SBM.
A total population of 92 women with unstable SBM from breast cancer who were treated with RT at our department between January 2000 and January 2012 was retrospectively investigated. We calculated overall survival (OS) and BS (time between first diagnosis of bone metastases until death) with the Kaplan-Meier method and assessed prognostic factors for BS with a Cox regression model.
Mean age at first diagnosis of breast cancer was 60.8 years ± SD 12.4 years. OS after 1, 2 and 5 years was 84.8, 66.3 and 50 %, respectively. BS after 1, 2 and 5 years was 62.0, 33.7 and 12 %, respectively. An age > 50 years (p < .001; HR 1.036 [CI 1.015–1.057]), the presence of a single bone metastasis (p = .002; HR 0.469 [CI 0.292–0.753]) and triple negative phenotype (p < .001; HR 1.068 [CI 0.933–1.125]) were identified as independent prognostic factors for BS.
Our analysis demonstrated a short survival of women with breast cancer and unstable SBM. Age, presence of a solitary SBM and triple-negative phenotype correlated with survival. Our results may have an impact on therapeutic decisions in the future and offer a rationale for future prospective investigations.
PMCID: PMC4501125  PMID: 26169373
Bone metastases; Breast cancer; Radiotherapy; Survival; Stability
19.  High-dose single-fraction IMRT versus fractionated external beam radiotherapy for patients with spinal bone metastases: study protocol for a randomized controlled trial 
Trials  2015;16:264.
Stereotactic body radiation therapy (SBRT)using intensity-modulated radiotherapy (IMRT) can be a safe modality for treating spinal bone metastasis with enhanced targeting accuracy and an effective method for achieving good tumor control and a rigorous pain response.
This is a single-center, prospective randomized controlled trial to evaluate pain relief after RT and consists of two treatment groups with 30 patients in each group. One group will receive single-fraction intensity-modulated RT with 1×24 Gy, and the other will receive fractionated RT with 10×3 Gy. The target parameters will be measured at baseline and at 3 and 6 months after RT.
The aim of this study is to evaluate pain relief after RT in patients with spinal bone metastases by means of two different techniques: stereotactic body radiation therapy and fractionated RT. The primary endpoint is pain relief at the 3-month time-point after RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed.
Trial registration identifier NCT02358720 (June 2, 2015).
PMCID: PMC4465731  PMID: 26054533
Bone metastases; Spine; SBRT; IMRT; Palliative radiotherapy
20.  Education to a Healthy Lifestyle Improves Symptoms and Cardiovascular Risk Factors – AsuRiesgo Study 
Arquivos Brasileiros de Cardiologia  2015;104(5):347-355.
Cardiovascular diseases are the current leading causes of death and disability globally.
To assess the effects of a basic educational program for cardiovascular prevention in an unselected outpatient population.
All participants received an educational program to change to a healthy lifestyle. Assessments were conducted at study enrollment and during follow-up. Symptoms, habits, ATP III parameters for metabolic syndrome, and American Heart Association’s 2020 parameters of cardiovascular health were assessed.
A total of 15,073 participants aged ≥ 18 years entered the study. Data analysis was conducted in 3,009 patients who completed a second assessment. An improvement in weight (from 76.6 ± 15.3 to 76.4 ± 15.3 kg, p = 0.002), dyspnea on exertion NYHA grade II (from 23.4% to 21.0%) and grade III (from 15.8% to 14.0%) and a decrease in the proportion of current active smokers (from 3.6% to 2.9%, p = 0.002) could be documented. The proportion of patients with levels of triglycerides > 150 mg/dL (from 46.3% to 42.4%, p < 0.001) and LDL cholesterol > 100 mg/dL (from 69.3% to 65.5%, p < 0.001) improved. A ≥ 20% improvement of AHA 2020 metrics at the level graded as poor was found for smoking (-21.1%), diet (-29.8%), and cholesterol level (-23.6%). A large dropout as a surrogate indicator for low patient adherence was documented throughout the first 5 visits, 80% between the first and second assessments, 55.6% between the second and third assessments, 43.6% between the third and fourth assessments, and 38% between the fourth and fifth assessments.
A simple, basic educational program may improve symptoms and modifiable cardiovascular risk factors, but shows low patient adherence.
PMCID: PMC4495449  PMID: 25789881
Health Behavior; Life Style; Prevention; Obesity; Risk Factors; Health Education
21.  Posttraumatic Inflammation as a Key to Neuroregeneration after Traumatic Spinal Cord Injury 
Pro- and anti-inflammatory cytokines might have a large impact on the secondary phase and on the neurological outcome of patients with acute spinal cord injury (SCI). We measured the serum levels of different cytokines (Interferon-γ, Tumor Necrosis Factor-α, Interleukin-1β, IL-6, IL-8, IL-10, and Vascular Endothelial Growth Factor) over a 12-week period in 40 acute traumatic SCI patients: at admission on average one hour after initial trauma; at four, nine, 12, and 24 h; Three, and seven days after admission; and two, four, eight, and twelve weeks after admission. This was done using a Luminex Performance Human High Sensitivity Cytokine Panel. SCI was classified using the American Spinal Injury Association (ASIA) Impairment Scale (AIS) at time of admission and after 12 weeks. TNFα, IL-1β, IL-6, IL-8, and IL-10 concentrations were significantly higher in patients without neurological remission and in patients with an initial AIS A (p < 0.05). This study shows significant differences in cytokine concentrations shown in traumatic SCI patients with different neurological impairments and within a 12-week period. IL-8 and IL-10 are potential peripheral markers for neurological remission and rehabilitation after traumatic SCI. Furthermore our cytokine expression pattern of the acute, subacute, and intermediate phase of SCI establishes a possible basis for future studies to develop standardized monitoring, prognostic, and tracking techniques.
PMCID: PMC4425057  PMID: 25860946
spinal cord injury; neuroregeneration; cytokines; inflammation; trauma
22.  Association of angiogenic factors with prognosis in esophageal cancer 
BMC Cancer  2015;15:121.
Despite multimodal therapy esophageal cancer often presents with poor prognosis. To improve outcome, tumor angiogenesis and anti-angiogenic therapeutic agents have recently gained importance. However, patient subgroups who benefit from anti-angiogenic therapy are not yet defined. In this retrospective exploratory study we investigated 9 angiogenic factors in patients’ serum and tissue samples with regard to their association with clinicopathological parameters, prognosis and response in patients with locally advanced preoperatively treated esophageal cancer.
From 2007 to 2012 preoperative serum and corresponding tumor tissue (n = 54), only serum (n = 20) or only tumor tissue (n = 4) were collected from esophageal squamous cell carcinoma (SCC) (n = 34) and adenocarcinoma of the esophagogastric junction (AEG) (n = 44) staged cT3/4NanyM0/x after preoperative chemo(radio)therapy. Angiogenic cytokine levels in both tissue and serum were measured by multiplex immunoassay.
Median survival in all patients was 28.49 months. No significant difference was found in survival between SCC and AEG (p = 0.90). 26 patients were histopathological responders. Histopathological response was associated with prognosis (p = 0.05).
Angiogenic factors were associated with the following clinicopathological factors: tumor tissue expression of Angiopoietin-2 and Follistatin was higher in SCC compared to AEG (p = 0.022 and p = 0.001).
High HGF and Follistatin expression in the tumor tissue was associated with poor prognosis in all patients (p = 0.037 and p = 0.036). No association with prognosis was found in the patients’ serum. Neither patients’ serum nor tumor tissue showed an association between angiogenic factors and response to neoadjuvant therapy.
Two angiogenic factors (HGF and Follistatin) in posttherapeutic tumor tissue are associated with prognosis in esophageal cancer patients. Biological differences of AEG and SCC with respect to angiogenesis were evident by the different expression of 2 angiogenic factors. Results are promising and should be pursued prospectively, optimally sequentially pre- and posttherapeutically.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1120-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4362831  PMID: 25885021
Esophageal cancer; Prognosis; Angiogenic factors; Response
23.  Bone density as a marker for local response to radiotherapy of spinal bone metastases in women with breast cancer: a retrospective analysis 
We designed this study to quantify the effects of radiotherapy (RT) on bone density as a local response in spinal bone metastases of women with breast cancer and, secondly, to establish bone density as an accurate and reproducible marker for assessment of local response to RT in spinal bone metastases.
We retrospectively assessed 135 osteolytic spinal metastases in 115 women with metastatic breast cancer treated at our department between January 2000 and January 2012. Primary endpoint was to compare bone density in the bone metastases before, 3 months after and 6 months after RT. Bone density was measured in Hounsfield units (HU) in computed tomography scans. We calculated mean values in HU and the standard deviation (SD) as a measurement of bone density before, 3 months and 6 months after RT. T-test was used for statistical analysis of difference in bone density as well as for univariate analysis of prognostic factors for difference in bone density 3 and 6 months after RT.
Mean bone density was 194.8 HU ± SD 123.0 at baseline. Bone density increased significantly by a mean of 145.8 HU ± SD 139.4 after 3 months (p = .0001) and by 250.3 HU ± SD 147.1 after 6 months (p < .0001). Women receiving bisphosphonates showed a tendency towards higher increase in bone density in the metastases after 3 months (152.6 HU ± SD 141.9 vs. 76.0 HU ± SD 86.1; p = .069) and pathological fractures before RT were associated with a significantly higher increase in bone density after 3 months (202.3 HU ± SD 161.9 vs. 130.3 HU ± SD 129.2; p = .013). Concomitant chemotherapy (ChT) or endocrine therapy (ET), hormone receptor status, performance score, applied overall RT dose and prescription of a surgical corset did not correlate with a difference in bone density after RT.
Bone density measurement in HU is a practicable and reproducible method for assessment of local RT response in osteolytic metastases in breast cancer. Our analysis demonstrated an excellent local response within metastases after palliative RT.
PMCID: PMC4355128  PMID: 25884703
Bone density; Bone metastases; Breast cancer; Radiotherapy; Local response
24.  Methylglyoxal as a new biomarker in patients with septic shock: an observational clinical study 
Critical Care  2014;18(6):683.
The role of reactive carbonyl species, such as methylglyoxal (MG), has been overlooked within the context of the sepsis syndrome. The aims of this study were to assess the impact of MG formation in different inflammatory settings and to evaluate its use for early diagnosis as well as prognosis of the sepsis syndrome.
In total, 120 patients in three groups were enrolled in this observational clinical pilot study. The three groups included patients with septic shock (n = 60), postoperative controls (n = 30), and healthy volunteers (n = 30). Plasma samples from patients with septic shock were collected at sepsis onset and after 24 hours and 4, 7, 14, and 28 days. Plasma samples from postoperative controls were collected prior to surgery, immediately following the end of the surgical procedure as well as 24 hours later and from healthy volunteers once. Plasma levels of MG were determined by high-performance liquid chromatography. Additionally, plasma levels of procalcitonin, C-reactive protein, soluble CD14 subtype, and interleukin-6 were determined.
Patients with septic shock showed significantly higher plasma levels of MG at all measured times, compared with postoperative controls. MG was found to identify patients with septic shock more effectively—area under the curve (AUC): 0.993—than procalcitonin (AUC: 0.844), C-reactive protein (AUC: 0.791), soluble CD14 subtype (AUC: 0.832), and interleukin-6 (AUC: 0.898) as assessed by receiver operating characteristic (ROC) analysis. Moreover, plasma levels of MG in non-survivors were significantly higher than in survivors (sepsis onset: *P = 0.018 for 90-day survival; **P = 0.008 for 28-day survival). Plasma levels of MG proved to be an early predictor for survival in patients with septic shock (sepsis onset: ROC-AUC 0.710 for 28-day survival; ROC-AUC 0.686 for 90-day survival).
MG was identified as a marker for monitoring the onset, development, and remission of sepsis and was found to be more useful than routine diagnostic markers. Further studies are required to determine the extent of MG modification in sepsis and whether targeting this pathway could be therapeutically beneficial to the patient.
Trial registration
German Clinical Trials Register DRKS00000505. Registered 8 November 2010.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0683-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4301657  PMID: 25498125
25.  Long-term (20- to 25-year) Results of an Uncemented Tapered Titanium Femoral Component and Factors Affecting Survivorship 
Uncemented femoral components in primary total hip arthroplasty (THA) are commonly used today, but few studies have evaluated their survival into the third decade.
We evaluated (1) survivorship using femoral revision for any reason as the end point; (2) survivorship using femoral revision for aseptic loosening as the end point; and (3) patient-related and surgical risk factors for aseptic stem loosening at a minimum 20-year followup with an uncemented tapered titanium stem.
We reviewed the clinical and radiographic results of 354 THAs in 326 patients performed between January 1985 and December 1989 using an uncemented grit-blasted, tapered titanium femoral stem. Mean age at surgery was 57 years (range, 13–81 years). Kaplan-Meier survivorship analysis was used to estimate long-term survival. Minimum followup evaluation was 20 years (mean, 22 years; range, 20–25 years); at that time, 120 patients (127 hips) had died, and four patients (five hips) were lost to followup. Multivariate survival analysis using a Cox regression model was performed.
Survivorship at 22 years with revision of the femoral component for any reason as the end point was 86% (95% confidence interval [CI], 81%–90%). Survivorship for femoral revision for aseptic loosening as the end point was 93% at 22 years (95% CI, 90%–96%). Undersized stems (canal fill index ≤ 80%) and stems in hips with cup revision were at higher risk for aseptic loosening (hazard ratio, 4.2 and 4.3, respectively). There was a high rate of acetabular revision in this series (38%), mostly related to smooth-threaded, cementless sockets.
Uncemented femoral fixation was reliable into the third decade. Age, male sex, and diagnosis were not associated with a higher risk of aseptic loosening.
Level of Evidence
Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3773148  PMID: 23670671

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